Gastrointestinal Acute Radiation Syndrome (GI-ARS) results from excessive pro-inflammatory cytokines, and is a common toxicity following the radiotherapy of abdominal or pelvic tumors. Sphingosine kinase-2 (SK2) is a critical mediator of GI injury from inflammatory cytokines, and Apogee is developing an oral SK2 inhibitor (ABC294640) that has anticancer and anti-inflammatory activity. ABC294640 is currently in phase 1/2a clinical testing in patients with advanced solid tumors. We have shown that ABC294640 effectively attenuates tissue damage and mortality in mouse models of GI-ARS when given either prior to or following radiation. We hypothesize that ABC294640 will reduce GI-ARS following abdominal or pelvic radiation, thereby providing substantial benefit to many cancer patients. Because of the advanced stage of ABC294640 development, these Proof-of-Concept studies can be rapidly translated into new clinical trial protocols.